Afatinib restrains K-RAS-driven lung tumorigenesis

Moll, Herwig P. and Pranz, Klemens and Musteanu, Monica and Grabner, Beatrice and Hruschka, Natascha and László, Viktória and Moldvay, Judit and Dezső, Katalin and Győrffy, Balázs and Döme, Balázs (2018) Afatinib restrains K-RAS-driven lung tumorigenesis. SCIENCE TRANSLATIONAL MEDICINE, 10 (446). pp. 1-12. ISSN 1946-6234

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On the basis of clinical trials using first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), it became a doctrine that V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-RAS) mutations drive resistance to EGFR inhibition in non-small cell lung cancer (NSCLC). Conversely, we provide evidence that EGFR signaling is engaged in K-RAS-driven lung tumorigenesis in humans and in mice. Specifically, genetic mouse models revealed that deletion of Egfr quenches mutant K-RAS activity and transiently reduces tumor growth. However, EGFR inhibition initiates a rapid resistance mechanism involving non-EGFR ERBB family members. This tumor escape mechanism clarifies the disappointing outcome of first-generation TKIs and suggests high therapeutic potential of pan-ERBB inhibitors. On the basis of various experimental models including genetically engineered mouse models, patient-derived and cell line-derived xenografts, and in vitro experiments, we demonstrate that the U.S. Food and Drug Administration-approved pan-ERBB inhibitor afatinib effectively impairs K-RAS-driven lung tumorigenesis. Our data support reconsidering the use of pan-ERBB inhibition in clinical trials to treat K-RAS-mutated NSCLC.

Item Type: Article
Subjects: R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok, tumorok, onkológia
Depositing User: MTMT SWORD
Date Deposited: 06 Mar 2019 15:10
Last Modified: 06 Mar 2019 15:10

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